Purpose: :
The proper development of the photoreceptor outer segmentdepends on faithful expression of OS molecules, their transporters,and the integrity of connecting cilium (CC). Here, we reportthe effects of a mutation in Prefoldin 5, a subunit of Prefoldin,a heterohexameric chaperone that transports actins and tubulinsto a cytosolic containing TCP–1 (CCT) for proper foldingduring OS development. Actins and tubulins are crucial componentsof the CC.

Methods: :
A point mutation, T362G (L110R), in Prefoldin 5 wasidentified in a mutant mouse, NMF5a, generated by ENU mutagenesis.Effects of the mutation were studied using light–microscopy,ERG, and immunohistological methods.

Results: :
At 4 weeks ERGs obtained from mutant mice were abnormalwith a reduction in dark adapted a– and b–waves,indicating that photoreceptor cells were compromised. Severeouter retinal degeneration supported the ERG findings. BetweenP10.5 and P12.5, the outer nuclear layer thickness is the samein mutant and wild–type. However, the OS and IS appearthinner than those of littermate controls. Rhodopsin and rom1are mis–localized in the outer nuclear layer and innersegment in mutants, indicating that that transport via the CCto the OS may be impaired. Close examination of the region ofthe OS suggests that they may not develop at all.

Conclusions: :
Our results show for the first time that a mutationwithin Prefoldin 5 causes abnormal outer segment development.The core cytoskeleton of the CC mainly consists of microtubuleswith a cluster of actin filaments at the distal part of theCC; microtubule structures are known to be crucial for the transportof OS molecules from the IS and actin filaments appear to beimportant of the initial morphogenesis of OS disk membranes.Therefore, it is likely that the underlying molecular causeof this abnormal OS development may be in the integrity of theCC since Prefoldin 5 is mainly involved in proper folding oftubulin and actins. However, we cannot exclude the possibilitythat Prefoldin 5 might interact with other molecules importantfor retinal function that may be impaired as a result of theidentified mutation. It is also likely that the degenerationobserved may be due to the abnormal accumulation of moleculesin the IS and ONL that normally localized to the OS, inducinga state of cellular stress.